Proteogenomic Characterization Reveals Tumorigenesis and Progression of Lung Adenocarcinoma Manifested as Subsolid Nodules

Lung adenocarcinoma (LUAD) radiologically displayed as subsolid nodules (SSNs) is prevalent. However, precise clinical management of SSNs requires thorough understanding of its tumorigenesis and progression. Here, we analyzed 66 LUAD displayed as SSNs covering 3 histological stages including adenocarcinoma in situ (AIS), minimally invasive adenocarcinoma (MIA) and invasive adenocarcinoma (IAC) by incorporating genomics, proteomics, phosphoproteomics and glycoproteomics. Intriguingly, cholesterol metabolism is aberrantly regulated in the preneoplastic AIS stage. Furthermore, sustained endoplasmic reticulum stress was demonstrated to be a hallmark and a reliable biomarker of AIS progression to IAC. Consistently, targeted promotion of ER stress profoundly retarded LUAD progression. Our study provides comprehensive proteogenomic landscape of SSNs, sheds lights on the tumorigenesis and progression of SSNs and suggests preventive and therapeutic strategies for LUAD.